Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[CH:7]=1.[H-].[Na+].CI.[C:20](=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([N:8]([CH:9]2[CH2:11][CH2:10]2)[CH3:20])[CH:7]=1
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1cc(Cl)c(F)cc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
To a solution of 500 mg (2.17 mmol) (5-chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-amine (J. Med. Chem. 1992, 35(8), 1385) in 5 mL N,N-dimethylformamide was added 104 mg (2.385 mmol) sodium hydride (60% dispersion in mineral oil) and 339 mg (2.385 mmol) methyl iodide. The reaction mixture was stirred for 6 hours at room temperature and then poured on 30 mL 10% aqueous sodium bicarbonate solution and 30 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate 100:0 to 80:20) to give 433 mg (82%) of the desired compound as a yellow oil. MS (ESI): m/z=245.049 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:26])[C:24]=1[F:25])[N:21]=[CH:20][C:19]([C:27](OCC)=[O:28])=[C:18]2[OH:32].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:27]([C:19]2[CH:20]=[N:21][C:22]3[C:17]([C:18]=2[OH:32])=[CH:16][C:15]([F:14])=[C:24]([F:25])[C:23]=3[F:26])=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.45 mL) in 5 mL of toluene is added 1.84 mL of a 2.0 M solution of trimethylaluminum in toluene. The solution is stirred for 5 min at 0° C. and then 0.20 g of ethyl 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylate (Tetrahedron 48, 29 (1992)) is added. The solution is stirred at 0° C. for an additional 30 min and then it is stirred 18 h at 25° C. The mixture is poured onto a mixture of 50 mL of 3 M hydrochloric acid and 50 mL of crushed ice. The mixture is extracted with three successive 75 mL portions of ethyl acetate. The combined extracts are dried (MgSO4) and the solvent is evaporated at reduced pressure. The residue is dissolved in a small volume of ethyl acetate and hexanes is added until the solution becomes cloudy. The mixture is then allowed to stand for 1 h. Filtration of this mixture gives the desired amide as 0.25 g of a solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:6]=1[N:13](C(=O)C)[C:14](=[O:16])[CH3:15])C.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[C:14]([NH:13][C:6]1[C:7]([F:12])=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:4]([OH:20])=[O:3])(=[O:16])[CH3:15]
Reactant: CCOC(=O)c1cc(Cl)cc(F)c1N(C(C)=O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(F)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 5-chloro-2-diacetylamino-3-fluorobenzoic acid ethyl ester (185 mg, 0.61 mmol) in MeOH (4 ml) was added 1N NaOH (1288 μl, 1.29 mmol) and the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to RT and then diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was made acidic with 1N HCl to pH3 and then extracted with ethyl acetate (2×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the desired product (130 mg, 92%) as a white solid which did not require further purification. MS (ISP) 230.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][C:7]([OH:9])=O)[C:3]([OH:5])=O.[NH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:14][CH2:13][C@@H:12]([N:11]1[C:7](=[O:9])[CH2:6][C:2]([CH3:1])([CH3:10])[C:3]1=[O:5])[CH3:15])(=[O:18])[CH3:17]
Reactant: C[C@H](N)CO
Reactant: CC(C)(CC(=O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H](C)N1C(=O)CC(C)(C)C1=O
Temperature: 85 °C
Yield: 62.3 %

Procedure:
A suspension of 2,2-dimethylsuccinic acid (10.5 g, 71.7 mmol) in acetic anhydride (50 mL) was heated at 85° C. for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in toluene (150 mL) and (S)-2-aminopropan-1-ol (6.0 g, 80 mmol) was added. The mixture was heated at reflux for 1 h under nitrogen atmosphere and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was heated in acetic anhydride (50 mL) at 80° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified on a silica gel column (eluting with PE/EA=3/1) to afford (S)-2-(3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)propyl acetate (10.1 g, 62.3%). 1H-NMR (CDCl3) δ 4.41 (m, 2H), 4.25 (m, 1H), 2.50 (s, 2H), 1.97 (s, 3H), 0.137 (d, 3H), 1.29 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A mixture of 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-cyclohexanone (20.0 g, 53.3 mmol), 1-methylpiperazine (6.42 g, 128 mmol) and acetic acid (7.7 g, 128 mmol) in 1,2-dichloromethane (1 L) was stirred for 15 minutes at ambient temperature. Sodium triacetoxyborohydride (14.7 g, 69.3 mmol) was added and stirring was continued for 20 hours. Water (400 mL) was added followed by sodium bicarbonate (26.0 g, 310 mmol). The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with dichloromethane (300 mL). The combined organic extracts were dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The resulting oil was purified by flash chromatography on silica gel (275 g) using dichloromethane/methanol (9:1) as an eluent to give cis-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (10.2 g, 42%) and trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (5.8 g) which contained 10% of the cis isomer. This mixture was stirred in diethyl ether (100 mL) for 1.5 hours then the solid was collected by filtration to provide pure trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 20.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([OH:14])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1cc(-c2ccc(Cl)c(Cl)c2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)c(Cl)c2)on1
Yield: 84.2 %

Procedure:
5-(3,4-Dichlorophenyl)-3-hydroxyisoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.23 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.41 g, 85%) as a colorless powder.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][C:25]=4[Cl:33])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34](O)[CH3:35].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:34][CH3:35])=[O:31])=[CH:26][C:25]=4[Cl:33])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(C(=O)O)cc1Cl
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(C)nc3ccc(C(=O)NS(=O)(=O)c4ccccc4)nc32)c(Cl)c1
Yield: 67.5 %

Procedure:
To a solution of 5-(benzenesulfonylcarbamoyl)-3-(4-carboxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (25 mg, 0.052 mmol) in N,N-dimethylformamide (0.3 ml) were added ethanol (4 mg, 0.088 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12 mg, 0.062 mmol) and 1-hydroxybenzotriazole (10 mg, 0.075 mmol) at room temperature. Three hours later, ethyl acetate and water were added to the reaction mixture and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The organic layer was washed with water four times, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography (eluent: chloroform/methanol=10/1) and crystallized from ethyl acetate to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (18 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (9.20 g, 40.1 mmol), N,O-dimethylhydroxylamine hydrochloride (5.87 g, 60.2 mmol) and CH2Cl2 (120 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.54 g, 60.2 mmol), N,N-diisopropylethylamine (10.51 mL, 60.2 mmol) and 4-(dimethylamino)pyridine (250 mg, 2.046 mmol) before being stirred at RT overnight. After this time, the mixture was diluted with DCM (100 mL) and washed sequentially with 1 M hydrochloric acid (2×75 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The organic phase was dried (MgSO4) and then concentrated in vacuo to give tert-butyl 4-(methoxy(methyl)carbamoyl)-piperidine-1-carboxylate as a colorless oil (9.9 g), which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=O)[CH2:6][O:7][CH3:8].[C:11]1([NH2:18])[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=1.CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH2:18])[CH2:6][O:7][CH3:8]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCC(CC(=O)OC)Nc1ccccc1N
Reaction time: 6 h
Yield: 26.9 %

Procedure:
4-Methoxy-3-oxo-butyric acid methyl ester (0.67 mL, 5.0 mmol) and Benzene-1,2-diamine (560 mg, 5.5 mmol) are dissolved in DCM (20 mL) and HOAc (0.63 mL, 11 mmol) is added into it. The mixture is stirred for 6 hrs and then NaBH(OAC)3 (3.7 g, 17 mmol) is added and the mixture is stirred for another 60 hr. Then 50 mL of sat. NaHCO3 along with 50 mL of water are added and the mixture is extracted with EtOAc (3×100 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by flash column choromatography affords 320 mg (27%) of 3-(2-Amino-phenylamino)-4-methoxy-butyric acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1[CH2:40][O:39][CH2:38][CH2:37]1.COCCBr>CN(C=O)C>[CH3:40][O:39][CH2:38][CH2:37][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: COCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: COCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 15.3 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 2-bromoethyl methyl ether (0.083 mL; 0.884 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.018 g (15%) of the title compound as a colorless oil.
Reaction SMILES: [C:1](#N)[CH3:2].[O:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH2:9]>>[OH:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:5][CH2:6][CH2:7][CH2:8][CH2:1][CH3:2])=[O:4]
Reactant: CC#N
Reactant: C1CCOC1
Reactant: O
Product: CCCCCCCCCC(=O)O

Procedure:
Instrumentation: Preparative HPLC (Waters 4000) equipped with refractive index monitor (Waters 2414) and a radial compression module (Waters 8×100). A preparative C18 column (Nova-Pak HR 8×100) was used with a Shimadzu CR 501 chromatopac integrator. The mobile phase was prepared by mixing acetonitrile with tetrahydrofuran and water in a ratio of 5:1:4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([OH:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(N(C(C)C)CC)(C)C>[Cu](I)I.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([S:16][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: OC(=S)c1ccccc1
Reactant: Clc1ccc(I)cn1
Agent: I[Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Sc1ccc(Cl)nc1)c1ccccc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 23.9 g of 2-chloro-5-iodopyridine, 14 ml of thiobenzoic acid, 1.90 g of copper iodide, 3.60 g of 1,10-phenanthroline, 35 ml of diisopropylethylamine and 200 ml of toluene was stirred at 110° C. for 4 hours. Water was added to the reaction mixture cooled to room temperature, and the insoluble matter was filtered with celite (registered trademark), then the filtered matter was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 21.2 g of thiobenzoic acid S-(6-chloropyridin-3-yl)ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[C:9]([O:11]C)=[O:10])[CH3:4].O.Cl>CCOC(C)=O.CCCCCC>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[C:9]([OH:11])=[O:10])[CH3:4]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1cnn(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCOc1cc(C(=O)O)ccc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aqueous 5 N sodium hydroxide solution (0.6 mL, 3.0 mmol) was added to a methano chloroform (1/1) solution (5 mL) of methyl 3-ethoxy-4-(1-methylpyrazol-4-yl)benzoate (149 mg, 0.57 mmol), and stirred overnight at room temperature. 5 N hydrochloric acid water (0.6 mL, 3.0 mmol) was added to the reaction liquid. The aqueous layer was extracted twice with chloroform, washed with saturated saline water, and dried with magnesium sulfate. The solution was filtered and concentrated under reduced pressure to obtain the title compound as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:10]1[O:11][CH2:12][CH2:13][N:14]=1)[CH3:9]>O>[O:7]([CH2:12][CH2:13][NH:14][C:10](=[O:11])[CH2:8][CH3:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCC1=NCCO1
Solvent: O
Product: CCC(=O)NCCOc1ccccc1
Yield: 92 %

Procedure:
Phenol (13.1 moles) was heated to 150° and stirred under N2 as 2-ethyl-2-oxazoline (12.2 moles) was added over 1 hr. The mixture was heated to 175±3°. After heating 16 hr the oil was cooled to about 140°, and then it was poured into water (12 L) with vigorous stirring. The mixture was stirred and cooled, and at about 25° the mixture was seeded with crystalline amide product. The material solidified and the supernatant was decanted. The residual solid was stirred with 17 L of hot (85°) water. The mixture was cooled to 25°, seeded with the amide product, and the mixture refrigerated. The resulting granular solid was collected on a filter, rinsed with several portions of water and left to air dry. This gave a 92% yield of material, m.p. 61.5°-64°.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.C[O-].[Na+].[NH2:14][C:15]1[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[N:14]1[C:15]2[C:24](=[CH:23][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:16]=2)[C:25](=[O:26])[NH:27][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NC(=O)c1cc2ccccc2cc1N
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1nc2cc3ccccc3cc2c(=O)[nH]1
Yield: 79 %

Procedure:
Diethyl oxalate (2.35 g., 16.1 millimoles), sodium methoxide (10 mg. and 2-aminonaphthalene-3-carboxamide (1.50 g., 8.05 millimoles) are mixed together and heated at reflux for 2 days. The mixture is then cooled in an ice bath and the brown precipitate recovered by filtration. It is recrystallized from ethanol to give 1.76 g. (79% yield) of the desired ester. M.P. 240°-242° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:6]=2[CH:5]=1)([O-])=O.[O-2].[Al+3].[O-2].[O-2].[Al+3].ClCCl.C(O)C>CO>[N:12]1([CH2:11][C:9]2[O:10][C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]=3[N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc2nc(CN3CCCC3)oc2c1
Agent: [Al+3]
Agent: [O-2]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2nc(CN3CCCC3)oc2c1

Procedure:
Prepared analogously to Example VI.1.d from 1.80 g (7.28 mmol) of 6-nitro-2-(pyrrolidin-1-ylmethyl)benzoxazole (VIII.1.b) in methanol as solvent. Yield: 1.10 g (70% of theory); Rf value: 0.60 (aluminum oxide, dichloromethane/ethanol=20:1); C12H15N3O; EII mass spectrum: m/z=218 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:16][CH2:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C)c(OC(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Yield: 64.6 %

Procedure:
To a solution of methyl 3-isopropoxy-4-methylbenzoate (1.0 g, 4.8 mmol) in ethyl acetate (20 mL) were added N-bromosuccinimide (0.92 g, 5.19 mmol) and 2,2′-azobis(isobutyronitrile) (3 mg), and the mixture was heated under reflux for 6 hr. The reaction mixture was cooled, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (0.89 g, yield 64%) as a colorless oil. MS (ESI+): 287 (M+H), 289.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][S:6][C:7]1[C:11]([CH3:13])([CH3:12])[NH:10][C:9](=[O:14])[N:8]=1.[CH3:20]I>>[CH3:20][N:10]1[C:11]([CH3:13])([CH3:12])[C:7]([S:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=2[N:2]([CH3:1])[CH3:19])=[N:8][C:9]1=[O:14]
Reactant: CN(C)c1ccccc1CSC1=NC(=O)NC1(C)C
Reactant: CI
Product: CN(C)c1ccccc1CSC1=NC(=O)N(C)C1(C)C

Procedure:
Initially, 0.5 g of 4-(2-dimethylaminobenzylthio)-5,5-dimethyl-3-imidazolin-2-one was reacted with 1 mL of methyl iodide following the procedure used in Example 35. The desired compound was obtained in the form of a syrup. The yield of this compound was 0.43 g with a yield ratio of 81.9%. A result of a 1 H-NMR analysis of the compound is as follows:
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:2]([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1
Reactant: CN1CCC(C(Cl)c2ccc(F)cc2)CC1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CCC(C(c2ccc(F)cc2)N2CCNCC2)CC1
Yield: 62 %

Procedure:
A mixture of 4-(chloro(4-fluorophenyl)methyl)-1-methylpiperidine (1.2 g, 4.12 mmol) in butanone (10 ml), anhydrous piperazine (1.43 g, 16.48 mmol), anhydrous K2CO3 (0.54 g, 4.14 mmol) and KI (0.65 g, 4.14 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2C12 (50 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (CH2C12:CH3OH:NH4OH 90:10:0.5) afforded desired product in 62% yield.